Lung cancer causes more deaths in men and women than any other cancer in the United States. Late detection of disease and inability to effectively treat this malignancy with chemotherapy are the main reasons for low survival rates. There is an urgent medical need to develop new molecularly targeted drugs for treating lung cancer, although it has been challenging to identify targets that are unique to cancer cells. This phase 1 SBIR application is based on an innovative technology platform being developed by PDEi Pharmaceuticals LLC stemming from the company's discovery that phosphodiesterase 10 (PDE10) is elevated in lung cancer and essential for the survival and proliferation of lung tumor cells. PDE10 plays a central role in signal transduction and is an attractive cancer target because it has low expression levels in peripheral tissues, but is strongly induced during cancer, whereby inhibitors have potential for high efficacy and low toxicity. From an extensive medicinal chemistry effort to develop novel PDE10 inhibitors, a series of indene derivatives were synthesized and found to selectively inhibit lung tumor cell growth in vitro. A lead compound, MCI-020 was identified with attractive oral bioavailability and ability to obtain high lung concentrations compared to other tissues and plasma. MCI-020 was well tolerated and highly efficacious in an orthotopic mouse model of lung cancer. Because of the potential to improve potency and target selectivity of MCI-020, we propose the following aims for lead optimization. Aim 1 will synthesize a series of novel indene derivatives chemically related to MCI-020 and will evaluate in vitro anticancer activity and selectivity for PDE10. Aim 2 will assess drug-like properties of the derivatives by determining pharmacokinetics, tissue distribution, and maximum tolerated dosage to select a lead compound. Aim 3 will determine efficacy and toxicity of the lead compound in an orthotopic mouse model of lung cancer and will confirm mechanism of action using tissues from the mouse model. We anticipate a clinical candidate will result from this project that will be advanced to a phase II application involving GMP scale-up synthesis and GLP toxicity testing in support of an IND application for human clinical trials.